The deposition of aggregated amyloid beta (A?) and hyperphosphorylated tau proteins is directly associated with cell death and propagation of brain pathology in sporadic as well as familial forms of Alzheimer's disease (AD). The long-term objective of this research is to define the molecular mechanism responsible for diverse phenotypes and progression rates in AD, and to explore the role of structural polymorphism of A? and tau aggregates as a potential determinant of phenotypic variability of the disease. To this end, we propose an integrated multidisciplinary approach involving three principal investigators with complementary expertise. Our key specific objectives are to delineate the AD phenotype-dependent structural organization of A? and tau aggregates, establish structure/function relationship, and identify key structural attributes that control distinct pathogenic potential of prion-like strains of A? amyloid fibrils and tau filaments. In the brain tissue from phenotypically distinct cases of sporadic and familial AD, we will perform strain-typing of A? and tau aggregates using approaches that were developed and validated in prion research. Furthermore, we will characterize the overall structural differences between brain-derived A? and tau aggregates corresponding to different AD phenotypes using mass spectrometry-based methods and assess their seeding (replication) potency, an in vitro attribute that relates to the progression rate of disease. Finally, we will obtain high- resolution insight into the structure of in vitro generated high-fidelity replicas of brain-derived A? and tau filaments corresponding to distinct phenotypes of AD using solid-state NMR spectroscopy. Establishing the relationship between specific structural features of A? and tau strains should uncover critical aspects of the pathogenesis in distinct forms of AD, key factors responsible for very rapid rate of cognitive decline in significant subset of AD, and test the hypothesis that prion-like strains are responsible for phenotypic diversity and progression rate. This insight is critical for efforts to develop molecular markers that predict progression and phenotype of AD and ultimately for novel therapeutic strategies.